ProjectSummary Amajorgoalofmodernaddictionresearchistounderstandtheneuraladaptationsthatunderliethechronic, maladaptiveand,formany,treatment-?refractorybehaviorsproducedbydrugsofabuse,includingcocaine. Considerableoptimismexistsinthisregard,aspowerfulpreclinicaltoolsandwell-?establishedanimalmodels haveresultedindramaticadvancesinourunderstandingofthemolecularandcellularmechanismsofcocaine-? relatedplasticity[1].Nonetheless,aconsiderablegapremainsintheclinical-?translationaltestingandvalidation ofsuchpreclinicalfindingsinhumancocaineaddiction. Inseminalpreclinicalstudiesnearly20yearsago,Robinson&Kolb[2,3]demonstratedenduringincreasesin synaptic(i.e.,dendriticspine)densityinboththenucleusaccumbens[NAc]andmedialprefrontalcortex[mPFC]) ofrodentsfollowingbehaviorallysensitizingregimensofcocaine.Theirfindingswerecompellingandsuggested animportantpathophysiologicalmechanism?aberrantstructuralsynapticplasticity?wherebycocainemight producethechronic,recalcitrantbehaviors(e.g.,craving,compulsiveuse,andrelapse)soseemingly?hard-? wired?inthosesufferingfromthedisorder. Ourgrouphasdevelopedanovelradiotracer,11C-?UCB-?J,forimagingsynapticdensityinthelivinghumanbrain usingpositron-?emissiontomography(PET)[62,63].Thus,thecurrentCuttingEdgeBasicResearchAward (CEBRA)/R21applicationseekstoapplythisbreakthroughmethodologytoexplorewhetherobservationsof increasedsynapticdensityintheNAcandmPFCofrodentsarerecapitulatedincocainedependent(CD)humans. Ifachieved,thecurrentstudywouldhaveamajorimpact,providingpowerfulclinical-?translationalsupportfor aberrantbrainstructureatthesynapticlevel,settingthestageforfuturestudiesoftherelationshipofsuch aberrantsynapticdensitytowithdrawal/abstinence,cocaine-?relatedbehaviorandclinicaloutcome.